Therapeutic agents

Abstract

A compound of formula (I) or a compound of formula (II) or pharmaceutically acceptable salts thereof, wherein R1-R7 and X are as defined in the description, and the use of these compounds in therapy, in particular in treating cancer or as an inhibitor of the interaction of the MDM2 protein with p53.

The invention claimed is: 
     
       1. A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is O; 
 R 1  is selected from substituted aralkyl and substituted heteroaralkyl; 
 R 2  is substituted or unsubstituted alkylamine; 
 R 3  is 4-chlorophenyl; and 
 R 4 -R 7  represents groups R 4 , R 5 , R 6  and R 7  which are independently selected from hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylamine, substituted or unsubstituted alkoxy, trifluoromethyl, amino, nitro, carboxyl, carbonylmethylsulfone, trifluoromethylsulfone, cyano and substituted or unsubstituted sulfonamide. 
 
       
     
     
       2. A compound according to  claim 1 , wherein R 1  is substituted aralkyl. 
     
     
       3. A compound according to  claim 1 , wherein R 1  is substituted benzyl. 
     
     
       4. A compound according to  claim 1 , wherein R 1  is substituted 1-ethylphenyl, 4-nitrobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-iodobenzyl. 
     
     
       5. A compound according to  claim 4 , wherein the substituted 1-ethylphenyl is the S-enantiomer. 
     
     
       6. A compound according to  claim 1 , wherein R 4 -R 7  are all hydrogen or at least one of R 4 -R 7  is a chlorine atom. 
     
     
       7. A compound according to  claim 1 , wherein, where a moiety is substituted, substituent functional groups are selected from: halo, hydroxyl, hydroxyalkyl, acyl, acetamide, carboxyl, cyano, carboxamide (carbamoyl), sulfonamide, sulfone, sulfoxide, amino, alkoxy and silico ligand, and combinations thereof. 
     
     
       8. A pharmaceutical composition comprising an effective amount of at least one compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       9. A method of treating osteosarcoma, colorectal carcinoma, neuroblastoma, or uterus chorion cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       10. A method of inhibiting the interaction of MDM2 protein with p53 comprising administering a therapeutically effective amount of a compound of Formula I as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       11. A kit comprising at least one compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof; and instructions for use. 
     
     
       12. A kit according to  claim 11 , further comprising a second compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       13. A method of treating cancer in a mammal comprising administering a therapeutically effective amount of a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from breast cancer, advanced solid tumor, leukemia, acute myeloid leukemia (AML), sarcoma, acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), liposarcoma, lung cancer, and soft tissue sarcoma. 
     
     
       14. A method according to  claim 13 , wherein the cancer is leukemia. 
     
     
       15. A method according to  claim 13 , wherein the cancer is AML. 
     
     
       16. A method according to  claim 13 , comprising administering, in addition to the therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional anticancer agent. 
     
     
       17. A method according to  claim 9 , comprising administering, in addition to the therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional anticancer agent. 
     
     
       18. A method of manufacturing a medicament comprising, combining a compound of Formula I as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, with a carrier that comprises one or more accessory ingredients. 
     
     
       19. A compound according to  claim 7 , wherein R 1  is substituted 1-ethylphenyl, 4-nitrobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-iodobenzyl.